Acute fentanyl toxicity: from opioid-induced to hypoxia-mediated pathophysiology.

Fentanyl now accounts for most opioid overdose deaths, yet acute fentanyl toxicity is still primarily understood as respiratory depression. This view is incomplete. Fentanyl produces effects distinct from classical opioids, and looking at breathing control in isolation ignores the physiological mechanisms of O₂ delivery and O₂ sparing following overdose. This review proposes an integrated framework based on the physiology of O₂ delivery (DO₂). Fentanyl lethality results from a mismatch between DO₂ and O₂ consumption (V̇o₂) initiated by three centrally mediated toxicities: 1) central apnea and sustained hypoventilation reducing arterial O₂ content; 2) skeletal muscle rigidity impairing ventilation and causing hypermetabolism; and 3) cardiovascular depression via vagally mediated bradycardia and reduced cardiac output. Fentanyl reduces both determinants of DO₂ while increasing consumption, so the DO₂/V̇o₂ ratio collapses faster than hypoventilation alone predicts. The resulting hypoxia shifts the pathophysiology from opioid-dependent to hypoxia-dependent. Severe hypoxemia inhibits respiratory neurons and impairs myocardial contractility, creating a positive feedback loop no longer responsive to naloxone. Pre-existing ventilatory impairment, polysubstance exposure, and acute lung injury further narrow the recovery margin. Endogenous defenses, including gasping and opioid-resistant respiratory rhythms, may allow recovery if adequate DO₂ is restored in time. Fentanyl lethality is an O₂ crisis requiring therapeutic strategies that address the full DO₂/V̇o₂ mismatch.